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WO1996011927A1 - Antagonistes de l'endotheline - Google Patents

Antagonistes de l'endotheline Download PDF

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Publication number
WO1996011927A1
WO1996011927A1 PCT/US1995/013373 US9513373W WO9611927A1 WO 1996011927 A1 WO1996011927 A1 WO 1996011927A1 US 9513373 W US9513373 W US 9513373W WO 9611927 A1 WO9611927 A1 WO 9611927A1
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WO
WIPO (PCT)
Prior art keywords
amino
methyl
ethyl
indol
isovaleryl
Prior art date
Application number
PCT/US1995/013373
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English (en)
Inventor
Thomas Von Geldern
Jeffrey A. Kester
Andrew S. Tasker
Brian K. Sorensen
Saul H. Rosenberg
Charles W. Hutchins
Martin Winn
Original Assignee
Abbott Laboratories
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Publication of WO1996011927A1 publication Critical patent/WO1996011927A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to compounds which are endothelin antagonists, processes for making such compounds, synthetic intermediates employed in these processes and methods and compositions for antagonizing endothelin.
  • ET Endothelin
  • Big ET precursor peptide big endothelin
  • ECE endothelin converting enzyme
  • Endothelin has been shown to constrict arteries and veins, increase mean arterial blood pressure, decrease cardiac output, increase cardiac contractility in vitro, stimulate mitogenesis in vascular smooth muscle cells in vitro, contract non-vascular smooth muscle including guinea pig trachea, human urinary bladder strips and rat uterus in vitro, increase airway resistance in vivo, induce formation of gastric ulcers, stimulate release of atrial natriuretic factor in vitro and in vivo , increase plasma levels of vasopressin, aldosterone and catecholamines, inhibit release of renin in vitro and stimulate release of oonadotropins in vitro.
  • vasoconstriction is caused by binding of endothelin to its receptors on vascular smooth muscle (Nature 332 411 (1988), FEBS Letters 231 440 (1988) and Biochem. Biophys. Res. Commun. 154 868 (1988)).
  • An agent which suppresses endothelin production or an agent which binds to endothelin or which inhibits the binding of endothelin to an endothelin receptor will produce beneficial effects in a variety of therapeutic areas.
  • an anti-endothelin antibody has been shown, upon intrarenal infusion, to ameliorate the adverse effects of renal ischemia on renal vascular resistance and glomerular filtration rate (Kon, et al., J. Clin.
  • an anti-endothelin antibody attenuated the nephrotoxic effects of intravenously administered cyclosporin (Kon, et al., Kidney Int. 37 1487 (1990)) and attenuated infarct size in a coronary artery ligation-induced myocardial infarction model (Watanabe, et al., Nature 344 114 (1990)).
  • X is -N(R 2 )-, -O- or -S-, wherein R 2 is hydrogen, loweralkyl, arylalkyl or
  • Q is -O- or -CR 3 R 4 - wherein R 3 and R 4 are independently selected from
  • R 1 is loweralkyl, cycloalkyl, cycloalkylalkyl, arylalkyl, arylalkenyl, aryl,
  • alkoxy arylalkoxy, cycloalkoxy, cycloalkylalkoxy,
  • E is loweralkyl optionally substituted with one, two or three substituents independently selected from cyano, halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, thioalkoxy and azido;
  • G is hydrogen or loweralkyl
  • Ar is bicyclic aryl, bicyclic heteroaryl or aryl
  • Y is selected from the group consisting of
  • Z is selected from the group consisting of
  • W is -OR 10 wherein R 10 is hydrogen or a carboxy protecting group, amino, alkylamino, dialkylamino, hydroxyamino,
  • a preferred embodiment of the present invention is a compound of formula (II):
  • R 1 , Q, E, Ar, G, Ar, X, Y and Z are as defined above;
  • a more preferred embodiment of the present invention is a compound of formula (I) or (II) wherein
  • W is -OR 10 , wherein R 10 is hydrogen or a carboxy protecting group, amino, alkylamino, dialkylamino, hydroxyamino,
  • Another more preferred embodiment of the present invention is a compound of formula (I) or (II)
  • R 1 is loweralkyl, (alkyl)(cycloalkyl)amino, cycloalkoxy, arylamino,
  • Q is -O- or -CH(R 4 )- wherein R 4 is hydrogen or loweralkyl;
  • G is hydrogen
  • Ar is wherein R is hydrogen, loweralkyl or alkanoyl
  • Y is hydrogen, arylalkyl, haloalkyl, loweralkyl, aryl or cycloalkyl;
  • Z is (1) -CO-W, wherein W is -OR 10 wherein R 10 is hydrogen or a carboxy protecting group,
  • X is -N(R 2 )- or -O- wherein R 2 is hydrogen or loweralkyl
  • An even more preferred embodiment is a compound of formula (I) or (II) wherein
  • R 1 is (cycloalkyl)amino, arylamino, aryl, arylalkyl, spiroheterocyclic,
  • Q is -O- or -CH 2 -;
  • G is hydrogen
  • Ar is wherein R is loweralkyl
  • X is -NH- or -O-
  • Y is loweralkyl
  • the present invention also relates to processes for preparing the compounds of formula (I) and (II) and to the synthetic intermediates employed in these processes.
  • the present invention also relates to a method of antagonizing endothelin in a mammal in need of such treatment, comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or (II).
  • the invention further relates to endothelin antagonizing compositions comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of formula (I) or (II).
  • the compounds of the invention comprise two or more asymmetrically substituted carbon atoms.
  • all stereoisomers for example, racemic mixtures, mixtures of diastereomers, as well as single diastereomers
  • S and R configuration are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13 -30.
  • Gly glycine, tryptophan, valine and leucine, respectively.
  • amino acid abbreviations used herein follow the IUPAC-IUB Joint Commission on
  • naturally occuring amino acid refers to an ⁇ -amino acid selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, ornithine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.
  • the stereochemistry at the asymmetric center can be of the D- or L- configuration.
  • N-protecting group or “N-protected” as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undersirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, “Protective Groups In Organic Synthesis,” (John Wiley & Sons, New York (1981)), which is hereby incorporated by reference. N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl,
  • benzenesulfonyl p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl,
  • N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl,
  • carboxy protecting group refers to a carboxylic acid protecting ester group employed to block or protect the carboxylic acid functionality while the reactions involving other functional sites of the
  • Carboxy protecting groups are disclosed in Greene. "Protective Groups in Organic Synthesis” pp. 152-186 (1981), which is hereby incorporated herein by reference.
  • a carboxy protecting group can be used as a prodrug whereby the carboxy protecting group can be readily cleaved in vivo , for example by enzymatic hydrolysis, to release the
  • carboxy protecting groups are C 1 to C 8 loweralkyl (e.g., methyl, ethyl or tertiary butyl and the like);
  • haloalkyl alkenyl; cycloalkyl and substituted derivatives thereof such as cyclohexyl, cylcopentyl and the like; cycloalkylalkyl and substituted derivatives thereof such as cyclohexylmethyl, cylcopentylmethyl and the like; arylalkyl, for example, phenethyl or benzyl and substituted derivatives thereof such as alkoxybenzyl or nitrobenzyl groups and the like; arylalkenyl, for example, phenylethenyl and the like; aryl and substituted derivatives thereof, for example, 5-indanyl and the like; dialkylaminoalkyl (e.g., dimethylaminoethyl and the like); alkanoyloxyalkyl groups such as acetoxymethyl, butyryloxymethyl, valeryloxymethyl, isobutyryloxymethyl, isovaleryloxymethyl, 1-(propionyloxy)
  • cycloalkanoyloxyalkyl groups such as cyclopropylcarbonyloxymethyl, cyclobutylcarbonyloxymethyl, cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl and the like;
  • aroyloxyalkyl such as benzoyloxymethyl, benzoyloxyethyl and the like;
  • arylalkylcarbonyloxyalkyl such as benzylcarbonyloxymethyl, 2-benzylcarbonyloxyethyl and the like; alkoxycarbonylalkyl, such as
  • alkoxycarbonyloxyalkyl such as methoxycarbonyloxymethyl, t-butyloxycarbonyloxymethyl, 1-ethoxycarbonyloxy-1-ethyl, 1-cyclohexyloxycarbonyloxy-1-ethyl and the like; alkoxycarbonylaminoalkyl, such as t-butyloxycarbonylaminomethyl and the like; alkylaminocarbonylaminoalkyl, such as methylaminocarbonylaminomethyl and the like; alkanoylaminoalkyl, such as acetylaminomethyl and the like; heterocycliccarbonyloxyalkyl, such as 4-methylpiperazinylcarbonyloxymethyl and the like; dialkylaminocarbonylalkyl, such as dimethylaminocarbonylmethyl, diethyla
  • loweralkyl or “alkyl” as used herein refer to straight or branched chain alkyl radicals containing from 1 to 10 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.
  • alkylamino refers to R51 NH- wherein R 5 1 is a loweralkyl group, for example, ethylamino, butylamino, and the like.
  • alkylaminocarbonyl refers to an alkylamino group, as previously defined, appended to the parent molecular moiety through a carbonyl (-C(O)-) linkage.
  • alkylaminocarbonyl include
  • alkylaminocarbonylaminoalkyl refers to alkylaminocarbonylaminoalkyl
  • alkylaminocarbonylaminoalkyl examples include
  • dialkylamino refers to R 56 R 57 N- wherein R 56 and R 57 are independently selected from loweralkyl, for example diethylamino. methyl propylamino, and the like.
  • dialkylaminoalkyl refers to R 71 R 72 N-R 73 - wherein R 71 and R 72 are independently selected from loweralkyl and R 73 is an alkylene group.
  • dialkylaminoalkyl include dimethylaminomethyl, dimethylaminoethyl, N-ethyl-N-methylaminomethyl, and the like.
  • dialkylaminocarbonyl refers to a dialkylamino group, as previously defined, appended to the parent molecular moiety through a carbonyl (-C(O)-) linkage.
  • dialkylaminocarbonyl include dimethylaminocarbonyl, diethylaminocarbonyl and the like.
  • dialkylaminocarbonylalkyl refers to dialkylaminocarbonylalkyl
  • R 100 -C(O)-R 101 - wherein R 100 is a dialkylamino group and R 101 is an alkylene group, for example, dimethylaminocarbonylmethyl and the like.
  • (alkyl)arylamino refers to R 60 R 61 N- wherein R 60 is an aryl group and R 61 is a loweralkyl group.
  • (alkyl)(arylalkyl)amino refers to R 64 R 65 N- wherein R 64 is an arylalkyl group and R 65 is a loweralkyl group.
  • (alkyl)(cycloalkyl)amino refers to R 58 R 59 N- wherein R 58 is a cycloalkyl group and R 59 is a loweralkyl group.
  • alkanoyl refers to an alkyl group as previously defined appended to the parent molecular moiety through a carbonyl (-C(O)-) group.
  • alkanoyl include acetyl, propionyl and the like.
  • alkanoylaminoalkyl refers to R 93 -NH-R 94 - wherein R 93 is an alkanoyl group and R 94 is an alkylene group.
  • alkanoylaminoalkyl include acetylaminomethyl, acetylaminoethyl and the like.
  • alkanoyloxyalkyl refers to R 74 -O-R 75 - wherein R 74 is an alkanoyl group and R 75 is an alkylene group.
  • alkanoyloxyalkyl include acetoxymethyl, acetoxyethyl and the like.
  • alkenyl refers to a straight or branched chain hydrocarbon radical containing from 2 to 10 carbon atoms and also containing at least one carbon-carbon double bond.
  • Alkenyl groups include, for example, vinyl (ethenyl), allyl (propenyl), butenyl, 1-methyl-2-buten-1-yl and the like.
  • alkoxy refers to R 41 O- wherein R 4 1 is a loweralkyl group, as defined above.
  • alkoxy include, but are not limited to, ethoxy, tert-butoxy, and the like.
  • alkoxyalkoxy refers to R 80 O-R 81 O- wherein R 80 is loweralkyl as defined above and R 81 is alkylene.
  • Representative examples of alkoxyalkoxy groups include methoxymethoxy, ethoxymethoxy, t-butoxymethoxy and the like.
  • alkoxycarbonyl refers to an alkoxyl group as previously defined appended to the parent molecular moiety through a carbonyl group.
  • alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl and the like.
  • alkoxycarbonylaminoalkyl refers to
  • alkoxycarbonylalkyl refers to R 84 -C(O)-R 85 - wherein R 84 is an alkoxy group and R 85 is an alkylene group.
  • alkoxycarbonylalkyl include methoxycarbonylmethyl, methoxcarbonylethyl, ethoxycarbonylmethyl and the like.
  • alkoxycarbonyloxyalkyl refers to alkoxycarbonyloxyalkyl
  • alkoxycarbonyloxyalkyl include tert-butyloxycarbonyloxymethyl, tert-butyloxycarbonyloxyethyl, and the like.
  • alkylene denotes a divalent group derived from a straight or branched chain saturated hydrocarbon having from 1 to 10 carbon atoms by the removal of two hydrogen atoms, for example -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )-, -CH 2 CH 2 CH 2 -, -CH 2 C(CH 3 ) 2 CH 2 - and the like.
  • aryl refers to a mono- or bicyclic carbocyclic ring system having one or more aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.
  • aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.
  • bicyclic aryl as used herein includes naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.
  • Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide.
  • substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.
  • arylalkenyl refers to an alkenyl radical to which is appended an aryl group, for example, phenylethenyl (cinnamyl) and the like.
  • arylalkoxy refers to R 42 O- wherein R 42 is an arylalkyl group, for example, benzyloxy, and the like.
  • arylalkyl refers to an aryl group as previously defined, appended to a loweralkyl radical, for example, benzyl and the like.
  • arylalkylamino refers to R 55 NH- wherein R 55 is an arylalkyl group, for example benzylamino and the like.
  • arylamino refers to R 53 NH- wherein R 53 is an aryl group, for example, anilino, and the like.
  • aryloxy refers to R 45 O- wherein R 45 is an aryl group, for example, phenoxy, and the like.
  • aroyloxyalkyl refers to R 82 -C(O)-O-R 83 - wherein R 82 is an aryl group and R 83 is an alkylene group.
  • Examples of aroyloxyalkyl include benzoyloxymethyl, benzoyloxyethyl and the like.
  • cycloalkyl refers to an carbocyclic ring system having 3 to 10 carbon atoms and 1 to 3 rings including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, adamantyl, and the like.
  • Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, aryl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide.
  • cycloalkylalkyl refers to a cycloalkyl group appended to a loweralkyl radical, including but not limited to cyclohexylmethyl.
  • cycloalkoxy refers to R 43 O- wherein R 43 is a cycloalkyl group, for example, cyclohexyloxy, and the like.
  • cycloalkylalkoxy refers to R 44 O- wherein R 44 is a cycloalkylalkyl group, for example, cyclohexylmethoxy, and the like.
  • (cycloalkyl)amino refers to R 52 NH- wherein R 52 is a cycloalkyl group, for example, cyclohexylamino, and the like.
  • (cycloalkylalkyl)amino refers to R 54 NH- wherein R 54 is a cycloalkylalkyl group, for example, cyclohexylmethylamino, and the like.
  • diarylamino refers to R 30 R 31 N- wherein R 30 and R 31 are independently selected from aryl as defined above.
  • halogen or halo as used herein refers to I, Br, Cl or F.
  • haloalkyl refers to a lower alkyl radical, as defined above, bearing at least one halogen substituent, for example, chloro methyl, fluoroethyl or trifluoromethyl and the like.
  • heterocyclic ring or “heterocyclic” or “heterocycle” as used herein refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7-membered ring containing one, two or three nitrogen atoms; one oxygen atom; one sulfur atom; one nitrogen and one sulfur atom; one nitrogen and one oxygen atom; two oxygen atoms in non-adjacent positions; one oxygen and one sulfur atom in non-adjacent positions; or two sulfur atoms in non-adjacent positions.
  • heterocyclic also includes 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,3,5-oxadiazole, 1,3,5-thiadiazole and tetrazole.
  • the 5-membered ring has 0-2 double bonds and the 6- and 7-membered ring have 0-3 double bonds.
  • the nitrogen heteroatoms can be optionally quatemized.
  • heterocyclic also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or another heterocyclic ring (for example, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, decahydroquinolyl, tetrahydoisoquinolinyl, indolinyl, benzofuryl or benzothienyl, imidazopyridyl, pyrrolopyridyl and the like).
  • heterocyclic also includes tricyclic groups in which any of the above heterocyclic rings is fused to two benzene rings or two cyclohexane rings or two other heterocyclic rings (for example, carbazolyl, iminodibenzyl and the like).
  • Heterocyclics include: azirdinyl, azetidinyl, benzimidazolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl,
  • morpholinyl morpholinyl, thiomorpholinyl, naphthyridinyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolindinylpyridyl, pyrrolinyl, pyrrolopyridyl, pyrrolyl, quinolinyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, thiazolyl, and thienyl.
  • nitrogen containing heterocycles can be N-protected.
  • the term "(heterocyclic)alkyl” as used herein refers to a heterocyclic group as defined above appended to a loweralkyl radical as defined above.
  • (heterocyclic)amino refers to R 35 NH- wherein R 35 is a heterocyclic group.
  • Examples of (heterocyclic)amino include 4-pyridylamino, 3-pyridylamino, 2-pyridylamino and the like.
  • Examples of (heterocyclic)(alkyl)amino include
  • (heterocyclicalkyl)amino refers to R 35c NH- wherein R 35C is a heterocyclicalkyl group.
  • Examples of (heterocyclic)amino include 4-pyridylmethylamino,
  • Examples of (heterocyclicalkyl)(alkyl)amino include
  • heterocycliccarbonyloxyalkyl refers to
  • R 96 -C(O)-O-R 97 - wherein R 96 is a heterocyclic group and R 97 is an alkylene group, for example, 4-methylpiperazinylcarbonyloxymethyl and the like.
  • bicyclic heteroaryl refers to a monocyclic heterocycle as defined above to which is fused a benzene ring, a cyclohexane ring or a monocyclic heterocycle as defined above, with the proviso that at least one of the rings of the bicyclic group is aromatic.
  • bicyclic heteroaryl include indolyl, indolinyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzofuryl, benzothienyl and the like.
  • Bicyclic heteroaryl groups can be unsu'bstituted or monosubstituted or disubstituted with
  • nitrogen containing heterocycles can be N-protected.
  • hydroxyarylalkyl refers to an arylalkyl radical to which is appended on the alkyl part an -OH group, for example, 2-hydroxy-1-pheneth-2-yl and the like.
  • spirocarbocyclic or "spirocarbocycle” as used herein refers to a bicyclic hydrocarbon in which the ring pair has just one carbon-atom in common, which is designated the "spiro atom".
  • Spirocarbocyclic compounds can be unsubstituted or substituted with one, two or three groups selected from loweralkyl, hydroxy, alkoxy, halo, haloalkyl and carboxy.
  • spirocarbocycles include spiropentane, spirohexane, spiro[4.4]nonane, spiro[2.4]octane and the like.
  • spiroheterocyclic or "spiroheterocycle” as used herein refers to a bicyclic spirocyclic ring system containing carbon atoms and at least one heteroatom selected from oxygen, nitrogen and sulfur. Examples of
  • spiroheterocycles include 1-oxa-4-azaspiro[5.4]decane, 1,4-diazaspiro[5.4]decane, 1-azaspiro[5.4]decane and the like.
  • Spiroheterocyclics can be substituted in the same way as defined above for heterocyclics.
  • tetrazolyl refers to a radical of the formula or a tautomer thereof.
  • thioalkoxy refers to R 70 S- wherein R 70 is loweralkyl.
  • examples of thioalkoxy include, but are not limited to, methylthio, ethylthio and the like.
  • Representative compounds of the invention include:
  • Preferred compounds are selected from the group consisting of:
  • One process for preparing the compounds of the invention comprises reacting a compound of the formula:
  • R 1 , Q and E are as defined above.
  • Activated ester derivatives of carboxylic acids include acid halides such as acid chlorides, and activated esters including, but not limited to, formic and acetic acid derived anhydrides, anhydrides derived from alkoxycarbonyl halides such as isobutyloxycarbonylchloride and the like, N-hydroxysuccinimide derived esters, N-hydroxyphthalimide derived esters, N-hydroxybenzotriazole derived esters, N-hydroxy-5-norbornene-2,3-dicarboxamide derived esters, 2,4,5-trichlorophenol derived esters and the like.
  • acid halides such as acid chlorides
  • activated esters including, but not limited to, formic and acetic acid derived anhydrides, anhydrides derived from alkoxycarbonyl halides such as isobutyloxycarbonylchloride and the like, N-hydroxysuccinimide derived esters, N-hydroxyphthalimide derived esters, N-hydroxy
  • X is -N(R 2 )-, -O- or -S-, wherein R 2 is hydrogen, loweralkyl, arylalkyl or
  • (heterocyclic)alkyl (heterocyclic)alkyl; and Y is hydrogen; loweralkyl; loweralkyl substituted with one, two or three groups independently selected from cyano, hydroxy, alkoxy, amino, alkylamino, dialkylamino, azido, thioalkoxy, and halo; cycloalkyl;
  • the acylated glycine is coupled with an appropriately protected activated amino acid residue (P* is an nitrogen protecting group, Ar is bicyclic aryl, aryl orbicyclic heteroaryl and A* is an amino acid activating group, for example, chloride, fluoride or mixed anhydride) to give 3.
  • the heterocyclic ring is prepared using the appropriate reagents (for example, DBU, carbon tetrachloride and triphenylphosphine to prepare an oxazole; ammonium acetate to prepare an imidazole; and Lawesson's reagent to prepare a thiazole) to give compound 4.
  • Hydroxy ester 6 (wherein R* is a carboxyl protecting group) is dissolved in an inert solvent (for example, THF) and converted to an activated compound 7 (where B* is an activating group, for example, an imidazolide formed by reaction of 6 with carbonyldiimidazole or an acid halide and the like).
  • the activated compound 7 is optionally further activated (for example, by alkylation with methyl triflate) and when R 1 is a nucleophile (for example, an amine) it reacts directly with the activated carbonate to provide compound 8.
  • R 1 -CO 2 H can be reacted directly with the protected hydroxy carboxylic acid 6 under standard esterification conditions.
  • the carboxy protecting group is removed to afford R 1 -C(O)-O-CH(E)-CO 2 H (5).
  • the heterocyclic intermediate 4 is nitrogen deprotected, coupled with the fully elaborated amino acid (R 1 -C(O)-O-CH(E)-CO 2 H) residue described above or an activated ester derivative thereof and then the carboxy protecting group is removed (for example, hydrolysis of an alkyl ester or hydrogenolysis of a benzyl ester) to give the final product 9.
  • Scheme II illustrates the preparation of compounds wherein Q is -CH 2 -.
  • Compound 21 (wherein R* is a carboxy protecting group) is prepared using the method of Plattner, et al., J. Med. Chem. 31 2277 (1988). The free carboxylic acid functionality of compound 21 is coupled or activated and reacted to give compound 22.
  • R 1 is an amine
  • standard peptide coupling conditions eg 1-hydroxybenzothazole, N-methyl morpholine and EDCI
  • the carboxy protecting group is removed (for example, hydrolysis for an alkyl ester or hydrogenation for a benzyl ester) to give compound 23.
  • Compound 23 is then coupled with compound 4, prepared in Scheme I, and then treated under conditions to remove the heterocyclic carboxy protecting group to give the final product 24.
  • acyl glycine 16 hexamethyldisilazide and then is acylated with acetyl chloride to give the acyl glycine 16.
  • the acylated glycine is coupled with an appropriately protected N-methyl-tryptophan to give 17.
  • the heterocyclic ring is prepared using the appropriate reagents (for example, DBU, carbon tetrachloride and triphenylphosphine to prepare an oxazole, ammonium acetate to prepare an imidazole and Lawesson's reagent to prepare a thiazole) to give compound 18.
  • the heterocyclic intermediate is de-protected, coupled with compound 25 and the benzyl group hydrogenolyzed to give the final product 20.
  • Scheme VII illustrates the preparation of compounds comprising various Z substituents.
  • Compound 34 prepared for example by the procedures described in Scheme I, is dissolved in an inert solvent such as THF and reacted with carbonyldiimidazole followed by R 16 S(O) 2 NH 2 (wherein R 16 is as defined previously herein) to give the corresponding sulfonamide 35.
  • compound 36 prepared for example by the procedures described in Scheme II, is deprotected by catalytic hydrogenation of the benzyl ester and then reacted with isobutylchloroformate and ammonia in the presence of N-methylmorpholine to give the carboxamide compound.
  • the carboxamide is dehydrated with phosphorus oxychloride to give the nitrile compound 37.
  • the nitrile is deprotected (for example, using trifluoroacetic acid) and coupled under standard peptide coupling conditions (for example, 1-hydroxybenzotriazole, N-methylmorpholine, and EDCI) with carboxylic acid 38 to give amide 39.
  • the nitrile compound is reacted with hydroxylamine hydrochloride in the presence of ethanolic sodium ethoxide, followed by carbonyldiimidazole and a trace of DBU to give 4H-[1 ,2,4]oxadiazol-5-one 40.
  • the nitrile 39 can be reacted with sodium azide in the presence of trimethyltin chloride to give tetrazole 41.
  • Boc-D-(1-methyl)-tryptophan (10.0 g) was dissolved in THF (75 mL) and the solution cooled to -20 °C.
  • N-Methylmorpholine (3.45 mL) was added followed by the dropwise addition of isobutylchloroformate (4.0 mL).
  • the 2-acetylglycine ester from above was dissolved in DMF (60 mL) and added to the mixed anhydride at -20 °C.
  • N-Methylmorpholine (3.5 mL) was then added via syringe pump over a one hour period. After the addition was complete, the reaction was allowed to stir at room temperature for one hour.
  • Example 1A The compound resulting from Example 1A (7.25 g) was dissolved in pyridine (25 mL), acetonitrile (25 mL), and carbon tetrachloride (3 mL). DBU (4.5 mL) and triphenylphosphine (4.20 g) were added and the mixture stirred at ambient temperature for 18 hours. The solvents were evaporated and the residue taken up in EtOAc (50 mL), washed with saturated NaHCO 3 solution, 1 N H 3 PO 4 , and brine, dried over MgSO 4 , and evaporated in vacuo.
  • Example 1D The compound resulting from Example 1B (120 mg) was dissolved in 6 mL of trifluoroacetic acid and allowed to stir at ambient temperature for 1 hour. The solvents were removed in vacuo; the residue was neutralized with sodium bicarbonate solution, and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. The residue obtained was used without further purification.
  • Example 1D The compound resulting from Example 1B (120 mg) was dissolved in 6 mL of trifluoroacetic acid and allowed to stir at ambient temperature for 1 hour. The solvents were removed in vacuo; the residue was neutralized with sodium bicarbonate solution, and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. The residue obtained was used without further purification.
  • Example 1D Example 1D
  • Example 1D The compound resulting from Example 1D (6.40 g) was combined in 75 mL of THF with 4.63 g (1.0 eq) of carbonyldiimidazole. The resultant solution was stirred at ambient temperature for 6 hours. The solvents were removed in vacuo; the residue was taken up in EtOAc and then washed sequentially with 0.2 N H 3 PO 4 and brine. The organic layer was dried over Na 2 SO 4 , filtered through Celite®, and evaporated in vacuo to give the title compound.
  • the nitrogen line was exchanged for a balloon of hydrogen, and the mixture was stirred at ambient temperature for 4 hours.
  • the catalyst was removed by filtration through a pad of Celite®, and the solvents were removed in vacuo to provide 224 mg (65% overall yield) of the title compound.
  • Example 1G The compound resulting from Example 1G was dissolved in 20 mL of ethanol, 50 mg of 10% palladium on carbon was added, and the mixture was purged with nitrogen. The nitrogen line was exchanged for a balloon of hydrogen, and the mixture was stirred at ambient temperature for 4 hours. The catalyst was removed by filtration through a pad of Celite®, and the solvents were removed in vacuo. The residue was triturated with hexanes/ether; the resultant material was dissolved in 0.1% aqueous TFA/acetonitrile and lyophilized to give the title compound as a white powder (62 mg).
  • Example 1F The crude final product was triturated with hexanes/ether; the resultant material was dissolved in 0.1% aqueous TFA/acetonitrile and lyophilized to give the title compound as a white powder (75 mg).
  • the nitrogen line was exchanged for a balloon of hydrogen, and the mixture was stirred at ambient temperature for 4 hours.
  • the catalyst was removed by filtration through a pad of Celite®; the solvents were removed in vacuo.
  • the residue was taken up in ether and extracted with 1 N NaOH.
  • the basic extracts were acidified with 1 N H 3 PO 4 and extracted with EtOAc.
  • the combined organic extracts were concentrated in vacuo to give 600 mg (89% yield) of the title compound.
  • Example 8B 2- ⁇ (1R)-1-(N-(2S 2-(N-(2-Fluorophenyl)aminocarboxy)-isovaleryl)-amino)-2- (1-methyl-indol-3-yl)ethyl ⁇ -5-methyl-oxazole-4-carboxylic acid
  • the compound resulting from Example 8B was dissolved in 20 mL of ethanol, 50 mg of 10% palladium on carbon was added, and the mixture was purged with nitrogen. The nitrogen line was exchanged for a balloon of hydrogen, and the mixture was stirred at ambient temperature for 4 hours. The catalyst was removed by filtration through a pad of Celite®; the solvents were removed in vacuo.
  • Example 1F The title compound was prepared according to the procedures described in Example 1, substituting indoline for N-methylcyclohexylamine in Example 1F.
  • the crude final product was triturated with hexanes/ether; the resultant material was dissolved in 0.1% aqueous TFA/acetonitrile and lyophilized to give the title compound as a white powder (78 mg).
  • Example 1 E A sample of the compound resulting from Example 1 E (300 mg) was dissolved in 6 mL of nitromethane and cooled to 0 °C; methyl
  • the resultant solution was stirred at ambient temperature for 15 hours, the solvents were removed in vacuo, and the residue was taken up in EtOAc.
  • the resulting solution was washed sequentially with 1 :1 sodium bicarbonate solution/water, 1 N H 3 PO 4 and brine, dried over Na 2 SO 4 , filtered through Celite®, and concentrated in vacuo.
  • Example 17B 2- ⁇ (1R)-1-(N-(2R)-(2-(N-Cyclohexylaminocarbonylmethyl)-isovaleryl)-aminol-2- (1-methyl-indol-3-yl)ethyl ⁇ -5-methyl-oxazole-4-carboxylic acid
  • the compound resulting from Example 17B was dissolved in 20 mL of ethanol, 50 mg of 10% palladium on carbon was added, and the mixture was purged with nitrogen. The nitrogen line was exchanged for a balloon of hydrogen, and the mixture was stirred at ambient temperature for 4 hours.
  • the catalyst was removed by filtration through a pad of Celite®; the solvents were removed in vacuo.
  • the crude material was purified by trituration with
  • Example 20A (118 mg, 0.31 mmol) and cyclohexa-1,3-diene (0.06 mL, 0.62 mmol, 2 eq). The mixture was stirred at room temperature for 16 hours, after which time the catalyst was removed by filtration through Celite®. The solvent was removed in vacuo to afford the title compound (81 mg, 90%).
  • Example 20C 2- ⁇ (1R)-1-(N-(2S)-(2-(1-Naphthylcarboxy)-isovaleryl)-amino)-2-(1-methyl-indol- 3-yl)ethyl ⁇ -5-methyl-oxazole-4-carboxylic acid benzyl ester
  • THF 3 mL
  • DMF 6 mL
  • N-methyl morpholine 0.034 mL, 0.31 mmol, 1.1 eq
  • HOBt 42 mg, 0.31 mmol, 1.1 eq
  • EDCI 60 mg, 0.28 mmol, 1 eq
  • Example 20A The title compound was prepared using the procedures described in Example 20, substituting indole-2-carboxylic acid for 1-naphthoic acid in Example 20A. The product was dissolved in acetonitrile and 0.1% TFA and lyophilized to give a white solid.
  • Example 23 2- ⁇ (1R)-1-(N-(2S)-(2-(1-lsoquinolinylcarboxy)-isovaleryl)-amino)-2-(1-methyl- indol-3-yl)ethyl ⁇ -5-methyl-oxazole-4-carboxylic acid
  • the title compound was prepared using the procedures described in Example 20, substituting isoquinoline-1 -carboxylic acid for 1-naphthoic acid in Example 20A.
  • 1 H NMR 300 MHz, CD 3 OD
  • ⁇ 8.66 (1H, d, J 9Hz)
  • 8.42 (1H, d,
  • Example 20A The product was dissolved in acetonitrile and 0.1% TFA and lyophilized to give a white solid.
  • N-(Diphenylmethylene)glycine benzyl ester (4.1 g) was dissolved in THF (25 mL) and the solution cooled to -78 °C. Lithium hexamethyldisilazide (12.5 mL, 1 N solution in THF) was added slowly over 10 minutes, and the resulting yellow slurry was stirred at -78 °C for 30 minutes. The slurry was then transferred via cannula to a solution of acetyl chloride (0.93 mL) in THF (25 mL) at -78 °C. After the addition was complete, the reaction was allowed to warm to room temperature and stirring was continued for four hours.
  • Fmoc-D-(1-Methyl)-Tryptophan (5.75 g), prepared by the method of Cook, et al., Chem. Pharm. Bull. 12 88 (1965), was dissolved in THF (20 mL) and the solution cooled to -20 °C. N-Methylmorpholine (1.45 mL) was added followed by the dropwise addition of isobutylchloroformate (1.7 mL). After the addition was complete, the reaction was stirred for 30 minutes at -20 °C at which time the bath was removed. The 2-acetylglycine ester from above was dissolved in DMF (20 mL) and added to the mixed anhydride.
  • N-Methylmorpholine (1.45 mL) was then added via syringe pump over a one hour period. After the addition was complete, the reaction was allowed to stir at room temperature for one hour. Water (75 mL) was added and the layers separated. The organic layer was washed with saturated NaHCO 3 solution, 1 N H 3 PO 4 and brine, dried with MgSO 4 , and evaporated under reduced pressure to give an orange oil which was purified by flash chromatography on silica gel eluting with 15% EtOAc/hexane to give the product as a yellow solid (3.85 g, 49% yield for the two steps).
  • Example 25A The compound resulting from Example 25A (5.0 g) was dissolved in acetic acid (25 mL). Ammonium acetate (4.0 g) was added and the mixture heated at reflux for 16 hours. After cooling, the solvent was evaporated under reduced pressure and the residue taken up in saturated NaHCO 3 solution and extracted with EtOAc. The combined organic extracts were dried over MgSO 4 and evaporated in vacuo. The resulting orange oil was purified by flash chromatography on silica gel eluting with 25% EtOAc-hexane to afford 1.10 g (23%) of the title compound.
  • Example 25B The compound resulting from Example 25B (100 mg) was suspended in
  • Example 26B 2- ⁇ (1S)-1-(N-(2S)-(2-(N-Cyclohexylaminocarbpnylmethyl)-isovaleryl)-amino)-2- (1-methyl-indol-3-yl)ethyl ⁇ -5-methyl-imidazole-4-carboxylic acid benzyl ester
  • the title compound was prepared according to the procedures described in Example 25E, substituting the compound of Example 17A for the compound of Example 25D.
  • Example 26B 2- ⁇ (1S)-1-(N-(2S)-(2-(N-Cyclohexylaminocarbpnylmethyl)-isovaleryl)-amino)-2- (1-methyl-indol-3-yl)ethyl ⁇ -5-methyl-imidazole-4-carboxylic acid benzyl ester
  • Example 26A The compound resulting from Example 26A was reacted according to the procedure of Example 25F.
  • the crude material was triturated with ether; the resultant material was purified by reverse phase HPLC eluting with a gradient of 0 to 80% acetonitrile in 0.1% TFA. The appropriate fraction was lyophilized to give the title compound as a white solid (17 mg).
  • Example 27B except o-fluorophenylacetic acid was substituted for phenylacetic acid.
  • the product was dissolved in acetonitrile and 0.1% TFA and lyophilized to give a white solid.
  • 1 H NMR 300 MHz, CD 3 OD
  • Example 31 2- ⁇ (1R)-1-(N-(2S)-(2-(2-Methylphenylacetoxy)-isovaleryl)-amino)-2-(1-methyl- indol-3-yl)ethyl ⁇ -5-methyl-oxazole-4-carboxylic acid
  • the title compound was prepared by the procedures described in Example 27B except o-methylphenylacetic acid was substituted for
  • Example 20 The title compound was prepared by the procedures described in Example 20 except 2-phenylpropionic acid was substituted for 1-naphthylenecarboxylic acid in Example 20A. The product was dissolved in acetonitrile and 0.1% TFA and lyophilized to give a white solid.
  • Example 20 The title compound was prepared by the procedures described in Example 20 except 2,6-difluorophenylacetic acid was substituted for 1-naphthylenecarboxylic acid in Example 20A.
  • Example 38 2- ⁇ (1R)-1-(N-(2S)-(2-(2.4-Difluorophenylpropionyl)-isovaleryl)-amino)-2-(1- methyl-indol-3-yl)ethyl ⁇ -5-methyl-oxazole-4-carboxylic acid
  • the title compound was prepared by the procedures described in
  • Example 20 except 2,4-difluorophenylacetic acid was substituted for 1-naphthylenecarboxylic acid in Example 20A.
  • MS DCI/NH 3 ) m/e 568 (M+H) + , 585 (M+H+NH 3 ) + .
  • Example 39B Examples 1A-1C, substituting propionyl chloride for acetyl chloride in Example 1A.
  • Example 39A The compound resulting from Example 39A was coupled with the compound resulting from Example 1 F by the method described by in Example 1G, and the benzyl ester protecting group was removed as in Example 1H.
  • the crude product was triturated with 1 :1 ethyl ether-hexane, dissolved in
  • Example 39A 2- ⁇ (1R)-1-(N-(2S)-(2-(N-Phenyl-N-methylaminocarboxy)-isovaleryl)-amino)-2- (1-methyl-indol-3-yl)ethyl ⁇ -5-ethyl-oxazole-4-carboxylic acid
  • Example 39A 2- ⁇ (1R)-1-(N-(2S)-(2-(N-Phenyl-N-methylaminocarboxy)-isovaleryl)-amino)-2- (1-methyl-indol-3-yl)ethyl ⁇ -5-ethyl-oxazole-4-carboxylic acid
  • Example 6 The compound resulting from Example 6 (60 mg) was dissolved in 3 mL of THF, 30 mg of carbonyldiimidazole (CDI) was added, and the resultant solution was stirred at ambient temperature for 3 hours. 4-Isopropylbenzenesulfonamide (24 mg) and DBU (3 drops) were added, and stirring was continued for 20 hours. The solvents were removed in vacuo, and the residue was purified by preparative HPLC (Vydac ⁇ C18) eluting with a 20-90% gradient of CH 3 CN in 0.1% TFA. The desired fractions were lyophilized to give the title compound as a white solid (32 mg).
  • CDI carbonyldiimidazole
  • Example 1B The compound resulting from Example 1B (3.00 g) was dissolved in 50 mL of ethanol, 100 mg of 10% palladium on carbon was added, and the mixture was purged with nitrogen. The nitrogen line was exchanged for a balloon of hydrogen, and the mixture was stirred at ambient temperature for 4 hours. The catalyst was removed by filtration through a pad of Celite, and the solvents were removed in vacuo. The crude acid was dissolved in 40 mL of THF; 1.2 mL of N-methylmorpholine was added, and the solution was cooled to 0 °C. Iso- butylchloroformate (0.9 mL) was added streamwise, and the resultant mixture was stirred at 0 °C for 45 minutes.
  • Example 43B 2- ⁇ (1R)-1-(N-(2S)-[2-(N-Cyclohexyl-N-methylaminocarboxy)-isovaleryl]-amino)- 2-(1-methyl-indol-3-yl)ethyl ⁇ -5-methyl-oxazole-4-carbonitrile
  • the compound resulting from Example 43B was combined in 10 mL of THF and 3 mL of DMF with 550 mg of the compound resulting from Example 1F, 270 mg of HOBt, and 0.5 mL of NMM; 385 mg of EDCI was added, and the solution was stirred for 15 hours at ambient temperature.
  • Example 44A 2- ⁇ (1R)-1-(N-(2S)-[2-(N-Phenyl-N-methylaminocarboxy)-isovaleryl]-amino)-2- (1-methyl-indol-3-yl)ethyl ⁇ -5-methyl-oxazole-4-carbonitrile (2S)-2-(N-Phenyl-N-methylaminocarboxy)isovaleric acid (made by the method described in Example 1 F, but substituting N-methylaniline for N-methylcyclohexylamine) was coupled with the compound resulting from
  • Example 43B by the method described in Example 43C.
  • Example 44A 2- ⁇ (1R)-1-(N-(2S)-[2-(N-Phenyl-N-methylaminocarboxy)-isovaleryl)-amino)-2- (1-methyl-indol-3-yl)ethyl ⁇ -5-methyl-4-(4H-[1,2,4]oxadiazol-5-on-3-yl)oxazole
  • the compound resulting from Example 44A was converted to the title compound by the procedure in Example 43D.
  • the crude product was purified by preparative HPLC (Vydac ⁇ C18) eluting with a 10-80% gradient of CH 3 CN in 0.1% TFA. The desired fractions were lyophilized to give the title compound as a white solid.
  • the reaction was quenched by the addition of 0.5 mL of methanol followed by 1 mL of 1 N aqueous H 3 PO 4 , the mixture was concentrated/r. vacuo, the residue was taken up in EtOAc and washed with 1 N aqueous H 3 PO 4 .
  • the product (113 mg) was isolated by flash chromatography on silica gel, eluting with a step gradient of EtOAc going to 10% CH 3 OH in EtOAc. The product was dissolved in acetonitrile and 0.1% TFA and lyophilized to give a white solid.
  • N-Methylmorpholine 13 mL was added followed by the dropwise addition of isobutylchloroformate (15.6 mL). After the addition was complete, the reaction was stirred for 30 minutes at -20 °C at which time the bath was removed. The 2-acetylglycine ester from above was dissolved in DMF (50 mL) and added to the mixed anhydride. N-Methylmorpholine (13 mL) was then added via syringe pump over a one hour period. After the addition was complete, the reaction was allowed to stir at room temperature for one hour. Water (200 mL) was added and the layers separated.
  • Lawesson's reagent (0.45 g) was added and the mixture stirred at reflux for five hours. The solvent was evaporated under reduced pressure and the residue taken up in EtOAc (20 mL). The solution was washed with saturated NaHCO 3 solution, 1 N H 3 PO 4 and brine, dried with MgSO 4 and evaporated under reduced pressure to give a yellow oil which was purified by flash
  • N-Methylmorpholine (10 ⁇ L) was added and the mixture stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure and the residue taken up in EtOAc. The solution was washed with saturated NaHCO 3 solution, 1 N H 3 PO 4 and brine, dried with MgSO 4 , and evaporated in vacuo to give an orange oil which was purified by flash chromatography on silica gel eluting with 50% EtOAc-hexane.
  • MMQ MacLeod/MacQueen/Login cell line (prolactin secreting rat pituitary cells which are known to contain ET A receptors)] cells from 150 ml culture flasks were collected by centrifugation (1000xg for 10 min) and then homogenized in 25 ml of 10 mM Hepes (pH 7.4) containing 0.25 M sucrose and protease inhibitors [3 mM EDTA , 0.1 mM PMSF, and 5 ⁇ g/ml Pepstatin A] by a micro ultrasonic cell disruptor (Kontes). The mixture was centrifuged at 1000xg for 10 min. The supernatant was collected and centrifuged at 60,000xg for 60 min.
  • the precipitate was resuspended in 20 mM Tris, pH 7.4 containing the above protease inhibitors and centrifuged again. The final pellet was resuspended in 20 mM Tris, pH 7.4 containing protease inhibitors and stored at -80 °C until used. Protein content was determined by the Bio-Rad dye-binding protein assay.
  • Binding assays were performed in 96-well microtiter plates pretreated with 0.1% BSA. Membranes prepared from cells were diluted ⁇ 100 fold in Buffer B (20 mM Tris, 100 mM NaCl, 10 mM MgCI 2 , pH 7.4, with 0.2% BSA, 0.1 mM PMSF, 5 ⁇ g/ml Pepstatin A, 0.025% bacitracin, and 3 mM EDTA) to a final concentration of 0.2 mg/mL of protein.
  • Buffer B (20 mM Tris, 100 mM NaCl, 10 mM MgCI 2 , pH 7.4, with 0.2% BSA, 0.1 mM PMSF, 5 ⁇ g/ml Pepstatin A, 0.025% bacitracin, and 3 mM EDTA
  • PI Phosphatidylinositol
  • mice Male Sprague-Dawley rats (350-500 g) were anesthetized with sodium pentobarbital (50 mg/kg, i.p.). The thoracic aorta was quickly removed and placed in a Krebs-Henseleit (KH) buffer gassed with 95/5 O 2 /CO 2 to maintain pH at 7.4. Aortas were cleared of extraneous tissue and segmented into 4-5 mm wide rings which were then suspended in 2 mL jacketed tissue baths maintained at 37 °C. The tissue baths had been siliconized to prevent adsorption of peptides to glass. Vessels were attached via gold chain to an isometric force transducer linked with a physiograph for monitoring tension changes.
  • KH Krebs-Henseleit
  • Baseline tension was set at 2.0 g (aorta) or 0.5 g (pulmonary artery) and the tissues were allowed to equilibrate for 2.5 hours. During this period, the tissues were washed every 5 minutes with fresh KH and the tension continually adjusted to baseline. Thirty minutes into the equilibration period, tissues were maximally constricted with norepinephrine (NE, 1 ⁇ M) followed by a challenge with acetylcholine (ACh, 3 ⁇ M). A positive relaxant response to ACh confirmed the presence of vessel endothelium. NE and ACh were then completely washed out and the tissues were allowed to return to baseline. Baseline tension was readjusted if necessary prior to any subsequent manipulations.
  • NE norepinephrine
  • ACh acetylcholine
  • DRCs Dose-Response Curves
  • ET-1 DRCs 1 E-11 to 1 E-6 M, were performed in rat aorta (ETa) to establish agonist-receptor potencies in those tissues.
  • maximal constrictor efficacy was compared with constriction by K + depolarization (55 mM).
  • Antagonists tested were equilibrated 15 minutes prior to the onset of the ET-1 DRCs. Concentrations of antagonist across experimental sets were in half log increasing doses with a total of 5 different concentrations examined for each compound tested. ET-1 vehicle (control) curves were performed along side antagonist-treated curves. Drug Potency Determination and Analysis:
  • Tissues in each aorta subset were from the same animal and were treated with one of the concentrations in the antagonist test range - the data was thus paired for analysis.
  • Agonist-induced tensions from control and antagonist-treated curves were calculated and normalized against maximal contraction in those curves and the effective concentration of agonist causing 50% maximum constriction (EC 50 ) was calculated (Allfit), providing a comparative index of antagonism.
  • vasospasm can be demonstrated according to the methods described in
  • the ability of the compounds of the invention to treat acute renal failure can be demonstrated according to the method described in Kon, et al., J. Clin. Invest. 83 1762 (1989).
  • the ability of the compounds of the invention to treat chronic renal failure can be demonstrated according to the method described in Benigni, et al., Kidney Int. 44 440-444 (1993).
  • neointimal formation restenosis
  • proliferative diseases can be demonstrated according to the methods described in
  • Proliferative diseases include smooth muscle proliferation, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, diabetic retinopathy or other retinopathies, psoriasis, scleroderma, prostatic hyperplasia, cardiac hyperplasia, restenosis following arterial injury or other pathologic stenosis of blood vessels.
  • Pulmonary hypertension can be associated with congestive heart failure, mitral valve stenosis, emphysema, lung fibrosis, chronic obstructive pulmonary disease (COPD), acute repiratory distress syndrome (ARDS), altitude sickness, chemical exposure, or may be idiopathic.
  • COPD chronic obstructive pulmonary disease
  • ARDS acute repiratory distress syndrome
  • the compounds of the present invention can be used in the form of salts derived from inorganic or organic acids.
  • These salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, giycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate
  • the basic nitrogen-containing groups can be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.
  • loweralkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates
  • long chain halides such
  • acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.
  • Basic addition salts can be prepared in situ during the final isolation and purification of the compounds of formula (I), or separately by reacting the carboxylic acid function with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia, or an organic primary, secondary or tertiary amine.
  • Pharmaceutically acceptable salts include, but are not limited to, cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, aluminum salts and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
  • Other representative organic amines useful for the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine,
  • the compounds of the invention are useful for antagonizing endothelin in a human or other mammal.
  • the compounds of the present invention are useful (in a human or other mammal) for the treatment of hypertension, acute or chronic pulmonary hypertension, Raynaud's disease, congestive heart failure, myocardial ischemia, reperfusion injury, coronary angina, cerebral ischemia, cerebral vasospasm, chronic or acute renal failure, pre-eclampsia (pregnancy-induced hypertension), non-steroidal
  • immunosuppressant for example, cyclosporin or FK 506
  • induced nephrotoxicity endotoxin-induced toxicity
  • asthma fibrotic or proliferative diseases, including smooth muscle proliferation, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, diabetic
  • retinopathy or other retinopathies retinopathy or other retinopathies, psoriasis, scleroderma, prostatic
  • hyperplasia bladder dysfunction (for example, incontinence), cardiac hyperplasia, restenosis following arterial injury or other pathologic stenosis of blood vessels, IL-2 (and other cytokine) mediated cardiotoxicity and vascular permeability disorders, LPL-related lipoprotein disorders, cancers, nociception, plaletet aggregation, and thrombosis, transplantation-induced atherosclerosis or atherosclerosis in general.
  • Total daily dose administered to a host in single or divided doses may be in amounts, for example, from 0.001 to 1000 mg/kg body weight daily and more usually 0.1 to 100 mg/kg for oral administration or 0.01 to 10 mg/kg for parenteral administration. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.
  • the compounds of the present invention may be administered orally, parenterally, sublingually, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically
  • Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices.
  • transdermal administration such as transdermal patches or iontophoresis devices.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrastemal injection, or infusion techniques.
  • sterile injectable preparations for example, sterile injectable aqueous or oleagenous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3-propanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules.
  • the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate.
  • the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
  • Liquid dosage forms for oral administration may include
  • compositions may also comprise adjuvants, such as wetting agents,
  • the compounds of the present invention can also be administered in the form of liposomes.
  • liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically aceptable and metabolizable lipid capabale of forming liposomes can be used.
  • the present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like.
  • the preferred lipids are the phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic.
  • cardiovascular agents independently selected from diuretics, adrenergic blocking agents, vasodilators, calcium channel blockers, renin inhibitors, angiotensin converting enzyme (ACE) inhibitors, angiotensin II antagonists, potassium channel activators and other cardiovascular agents.
  • ACE angiotensin converting enzyme
  • diuretics include hydrochlorothiazide, chlorothiazide, acetazolamide, amiloride, bumetanide, benzthiazide, ethacrynic acid, furosemide, indacrinone, metolazone, spironolactone, triamterene,
  • Representative adrenergic blocking agents include phentolamine, phenoxybenzamine, prazosin, terazosin, tolazine, atenolol, metoprolol, nadolol. propranolol, timolol, carteolol and the like or a pharmaceutically acceptable salt thereof.
  • vasodilators include hydralazine, minoxidil, diazoxide, nitroprusside and the like or a pharmaceutically acceptable salt thereof.
  • Representative calcium channel blockers include amrinone, bencyclane, diltiazem, fendiline, flunarizine, nicardipine, nimodipine, perhexilene,
  • verapamil, gallopamil, nifedipine and the like or a pharmaceutically acceptable salt thereof.
  • renin inhibitors include enalkiren,
  • angiotensin II antagonists include:
  • Representative ACE inhibitors include captopril, enalapril, lisinopril and the like or a pharmaceutically acceptable salt thereof.
  • Representative potassium channel activators include pinacidil and the like or a pharmaceutically acceptable salt thereof.
  • cardiovascular agents include sympatholytic agents such as methyldopa, clonidine, guanabenz, reserpine and the like or a pharmaceutically acceptable salt thereof.
  • the compounds of the invention and the cardiovascular agent can be administered at the recommended maximum clinical dosage or at lower doses.
  • Dosage levels of the active compounds in the compositions of the invention may be varied so as to obtain a desired therapeutic response depending on the route of administration, severity of the disease and the response of the patient.
  • the combination can be administered as separate compositions or as a single dosage form containing both agents.
  • the therapeutic agents When administered as a combination, the therapeutic agents can be formulated as separate compositions which are given at the same time or different times, or the therapeutic agents can be given as a single composition.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé de la formule (I) ou un sel pharmaceutiquement acceptable de celui-ci. L'invention concerne également des procédés de préparation d'un tel composé et les intermédiaires utilisés à cet effet, ainsi que des procédés et des compositions permettant de créer un antagonisme vis-à-vis de l'endothéline.
PCT/US1995/013373 1994-10-12 1995-10-10 Antagonistes de l'endotheline WO1996011927A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US32211494A 1994-10-12 1994-10-12
US08/322,114 1994-10-12
US44212495A 1995-05-30 1995-05-30
US08/442,124 1995-05-30

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WO1996011927A1 true WO1996011927A1 (fr) 1996-04-25

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US5925731A (en) * 1995-09-26 1999-07-20 Takeda Chemical Industries, Ltd. Endothelin antagonist peptides
US6030975A (en) * 1997-03-14 2000-02-29 Basf Aktiengesellschaft Carboxylic acid derivatives, their preparation and use in treating cancer
US6063911A (en) * 1993-12-01 2000-05-16 Marine Polymer Technologies, Inc. Methods and compositions for treatment of cell proliferative disorders
WO2002010140A3 (fr) * 2000-08-01 2002-08-08 Sod Conseils Rech Applic Dérivés imidazolyles
US7238695B2 (en) 1998-06-12 2007-07-03 Societe De Conseils De Recherches Et D'applications Scientifiques, Sas Imidazolyl derivatives
US8858964B2 (en) 2010-04-15 2014-10-14 Marine Polymer Technologies, Inc. Anti-bacterial applications of poly-N-acetylglucosamine nanofibers
US8871247B2 (en) 2007-02-19 2014-10-28 Marine Polymer Technologies, Inc. Hemostatic compositions and therapeutic regimens
WO2019025467A1 (fr) * 2017-07-31 2019-02-07 NodThera Limited Inhibiteurs sélectifs de l'inflammasome nlrp3
US10765698B2 (en) 2011-04-15 2020-09-08 Marine Polymer Technologies, Inc. Treatment of disease with poly-N-acetylglucosamine nanofibers
US11485705B2 (en) 2015-07-24 2022-11-01 Lumos Pharma, Inc. Salts and prodrugs of 1-methyl-d-tryptophan

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Publication number Priority date Publication date Assignee Title
EP0460679A2 (fr) * 1990-06-07 1991-12-11 Banyu Pharmaceutical Co., Ltd. Dérivés peptidiques ayant une activité antagoniste d'endothéline
WO1995008550A1 (fr) * 1993-09-24 1995-03-30 Abbott Laboratories Antagonistes d'endotheline

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
EP0460679A2 (fr) * 1990-06-07 1991-12-11 Banyu Pharmaceutical Co., Ltd. Dérivés peptidiques ayant une activité antagoniste d'endothéline
WO1995008550A1 (fr) * 1993-09-24 1995-03-30 Abbott Laboratories Antagonistes d'endotheline

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6063911A (en) * 1993-12-01 2000-05-16 Marine Polymer Technologies, Inc. Methods and compositions for treatment of cell proliferative disorders
US5925731A (en) * 1995-09-26 1999-07-20 Takeda Chemical Industries, Ltd. Endothelin antagonist peptides
US6030975A (en) * 1997-03-14 2000-02-29 Basf Aktiengesellschaft Carboxylic acid derivatives, their preparation and use in treating cancer
US7238695B2 (en) 1998-06-12 2007-07-03 Societe De Conseils De Recherches Et D'applications Scientifiques, Sas Imidazolyl derivatives
EP1139752A4 (fr) * 1998-12-22 2003-01-02 Marinepolymer Tech Inc Techniques et compositions permettant de traiter les troubles associes aux cellules proliferatives
JP2003522732A (ja) * 1998-12-22 2003-07-29 マリン ポリマー テクノロジーズ，インコーポレーテッド 細胞増殖性疾患を治療するための方法および組成物
JP4795539B2 (ja) * 1998-12-22 2011-10-19 マリン ポリマー テクノロジーズ，インコーポレーテッド 細胞増殖性疾患を治療するための方法および組成物
WO2002010140A3 (fr) * 2000-08-01 2002-08-08 Sod Conseils Rech Applic Dérivés imidazolyles
AU2001279098B2 (en) * 2000-08-01 2005-04-14 Societe De Conseils De Recherches Et D'applications Scientifiques, S.A.S Imidazolyl derivatives
US7566734B2 (en) 2000-08-01 2009-07-28 Societe De Conseils De Recherches Et D'applications Scientifiques, S.A.S. Imidazolyl derivatives
US7638546B1 (en) 2000-08-01 2009-12-29 Ipsen Pharma S.A.S. Imidazolyl derivatives
US9139664B2 (en) 2007-02-19 2015-09-22 Marine Polymer Technologies, Inc. Hemostatic compositions and therapeutic regimens
US10383971B2 (en) 2007-02-19 2019-08-20 Marine Polymer Technologies, Inc. Hemostatic compositions and therapeutic regimens
US9139663B2 (en) 2007-02-19 2015-09-22 Marine Polymer Technologies, Inc. Hemostatic compositions and therapeutic regimens
US8871247B2 (en) 2007-02-19 2014-10-28 Marine Polymer Technologies, Inc. Hemostatic compositions and therapeutic regimens
US10561677B2 (en) 2010-04-15 2020-02-18 Marine Polymer Technologies, Inc. Anti-bacterial applications of poly-N-acetylglucosamine nanofibers
US9642871B2 (en) 2010-04-15 2017-05-09 Marine Polymer Technologies, Inc. Anti-bacterial applications of poly-N-acetylglucosamine nanofibers
US10206938B2 (en) 2010-04-15 2019-02-19 Marine Polymer Technologies, Inc. Anti-bacterial applications of poly-N-acetylglucosamine nanofibers
US9198928B2 (en) 2010-04-15 2015-12-01 Marine Polymer Technologies, Inc. Anti-bacterial applications of poly-N-acetylglucosamine nanofibers
US8858964B2 (en) 2010-04-15 2014-10-14 Marine Polymer Technologies, Inc. Anti-bacterial applications of poly-N-acetylglucosamine nanofibers
US10765698B2 (en) 2011-04-15 2020-09-08 Marine Polymer Technologies, Inc. Treatment of disease with poly-N-acetylglucosamine nanofibers
US11485705B2 (en) 2015-07-24 2022-11-01 Lumos Pharma, Inc. Salts and prodrugs of 1-methyl-d-tryptophan
WO2019025467A1 (fr) * 2017-07-31 2019-02-07 NodThera Limited Inhibiteurs sélectifs de l'inflammasome nlrp3
KR20200115448A (ko) * 2017-07-31 2020-10-07 노드테라 리미티드 Nlrp3 인플라마좀의 선택적 억제제
JP2020529405A (ja) * 2017-07-31 2020-10-08 ノッドセラ リミテッド 選択的ｎｌｒｐ３インフラマソーム阻害剤
AU2018311198B2 (en) * 2017-07-31 2023-02-02 NodThera Limited Selective inhibitors of NLRP3 inflammasome
KR102704546B1 (ko) * 2017-07-31 2024-09-09 노드테라 리미티드 Nlrp3 인플라마좀의 선택적 억제제
US12247011B2 (en) 2017-07-31 2025-03-11 NodThera Limited Selective inhibitors of NLRP3 inflammasome

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